DESCRIPTION: (provided by the applicant) Nicotine addiction is a major health problem in the world, yet little is known about the molecular and cellular mechanisms that mediate its addicting effects. The goal of this project is to develop "Drosophila melanogaster" as an animal model to identify the genes and signaling pathways that regulate acute sensitivity to nicotine, the development of tolerance, and withdrawal. For this purpose we plan to carry out a genetic screen for mutants that show aberrant behaviors upon acute and chronic exposure to nicotine. The acute effects of nicotine will be measured with assays for locomotion, geotaxis, and postural nicotine. Tolerance will be quantified as the change in acute responses caused by pre-feeding nicotine for several days. Mutants that show altered responses that are not accounted for by changes in sensory systems will be characterized molecularly. We also propose to develop assays to quantify withdrawal from chronic nicotine exposure. These include assays for general hyperactivity and startle responses to chemosensory and mechanosensory stimuli. Flies are easy and inexpensive to rear, and nearly a century of extensive analysis has provided innumerable and sophisticated tools for genetic and molecular analysis. These attributes, together with the high degree of evolutionary conservation and the relevant neurochemical systems, allow us to carry out unbiased screens for novel molecules involved in nicotine responses, an approach that would be very expensive and laborious to implement in mammals. The genes identified in "Drosophila" should provide potential candidate genes and signaling pathways to be studied in rodent models and in human genetic studies.